First-pass disposition of (-)-6-aminocarbovir in rats. I. Prodrug activation may be limited by access to enzyme.

Important note: Information in this article was accurate in 1999. The state of the art may have changed since the publication date.

First-pass disposition of (-)-6-aminocarbovir in rats. I. Prodrug activation may be limited by access to enzyme.

Drug Metab Dispos. 1999 Jan;27(1):113-21. Unique Identifier : AIDSLINE MED/99102143
Wen Y; Remmel RP; Zimmerman CL; Departments of Pharmaceutics and Medicinal Chemistry, University; of Minnesota, College of Pharmacy, Minneapolis, Minnesota 55455,; USA.

Abstract: Several in vitro and in situ approaches were used to determine the dominant presystemic activation site for (-)-6-aminocarbovir, (-)-carbocyclic 2',3'-didehydro-2', 3'-dideoxy-6-deoxy-6-aminoguanosine (6AC) conversion in rats. The in vitro disappearance half-lives (mean +/- S.D.) in the cytosolic fractions obtained from homogenates of the intestine, liver, and intestinal contents were 0.4 +/- 0.1 (n = 3), 12.2 +/- 1.1 (n = 3), and 15.5 (n = 1) min, respectively. An in situ vascularly perfused intestine-liver (IPIL) study was then carried out (n = 6) to determine the relative contribution of each presystemic organ to the overall first-pass extraction of 6AC. The 6AC extraction ratios in the intestine and liver in the IPIL were found to be 0.08 +/- 0.02 and 0.11 +/- 0.03, respectively. The intestinal extraction ratio was in dramatic contrast to the in vitro results. It was postulated that vascularly delivered 6AC had limited access to the metabolic site in the intestine. A theoretical analysis suggested that the extent of intestinal wall extraction of 6AC would be underestimated by the IPIL and should be determined after oral dosing. To compare intestinal extraction ratio in the IPIL with that after an oral administration, in situ intestinal lumen perfusions (n = 4) and intraportal infusions (n = 3) of 6AC were conducted in two groups of rats. The lumenally administered 6AC was extracted to a much greater extent by the intestine as compared with the IPIL, which presents 6AC to the intestine by the vascular route. The extraction ratio was found to be 0.54 +/- 0.06, which was significantly larger than that obtained in the IPIL.

Keywords: JOURNAL ARTICLE Animal Anti-HIV Agents/*PHARMACOKINETICS Biotransformation Comparative Study Dideoxynucleosides/*PHARMACOKINETICS In Vitro Intestines/ENZYMOLOGY/*METABOLISM Liver/ENZYMOLOGY/*METABOLISM Male Models, Biological Prodrugs/*PHARMACOKINETICS Rats Rats, Sprague-Dawley Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S.
990530
A9950883

AEGiS is a 501(c)3, not-for-profit, tax-exempt, educational corporation. AEGiS is made possible through unrestricted funding from Boehringer Ingelheim, Bridgestone/Firestone Charitable Trust, Bristol-Myers Squibb Company, Elton John AIDS Foundation, Gill Foundation, the National Library of Medicine, Quest Diagnostics, Roche and Trimeris, and donations from users like you. Always watch for outdated information. This article first appeared in 1999. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 1999. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content. .